Ramipril(I), (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-amino]propanoyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid, represented by the formula (I) is a valuable angiotensin-converting enzyme (ACE) inhibitor, a family of drugs used to treat high blood pressure and some types of heart failure.

Ramipril(I) is marketed under the brandname ALTACE®. It has five chiral centers which leads to 32 optical isomers, of which the isomer with all S-configuration exhibits highest ACE inhibiting activity. The other optical isomers are comparatively less active or are completely inactive, hence undesirable.
Ramipril(I) of formula (I) is disclosed in U.S. Pat. No. 5,061,722 (assigned to Hoechst AG) which describes a process for the preparation of Ramipril(I) comprising condensation of benzyl cis,endo-2-azabicyclo-[3.3.0]-octane-3-S-carboxylate hydrochloride of formula (II) with N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanine of formula (III) in presence of a coupling agent such as dicyclohexylcarbodiimide in an organic solvent such as dimethylformamide. The diastereomeric mixture of (S,S,S,S,S) and (R,R,R,S,S) isomers of Ramipril(I) benzyl ester thus obtained is separated at this stage by silica gel chromatography using ethyl acetate/petroleum ether as the eluting solvent. The optically pure (S,S,S,S,S) benzyl ester is deprotected by hydrogenolysis or treatment with an acid or base to give Ramipril(I) of formula (I) which is on further recrystallised from ether, gives a product which has a melting point of 110-112° C.

Chromatographic separation of diastereomers is, however, a process of academic interest only and cannot be practiced advantageously on an industrial scale.
U.S. Pat. No. 6,407,262 (assigned to Brantford Chemicals Inc.) discloses a process for separating diastereomeric mixtures of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]octahydro-cyclopenta[b]pyrrole-2-carboxylic acid or its derivative and (2R,3aR,6aR)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]octahydro cyclopenta[b]pyrrole-2-carboxylic acid or its derivative by treating the diastereomeric mixture with a solvent or a mixture of solvents. The solvent or a mixture of solvents employed is selected from a group consisting of C2-C4 nitrile, C1-C6 alcohol, C6-C8 aromatic hydrocarbon, C3-C10 ether, C3-C6 ketone, C2-C7 ester, C1 to C3 chlorinated compounds, and C5-C10 hydrocarbon solvents.
Although, the abovementioned method claims to give Ramipril(I) of more than 99% purity, suffers from the disadvantages of utilizing the solvents which are not recommended by Regulatory and Environmental bodies, since these solvents belong to the list of Class II solvents as categorized by International Conference on Harmonization (ICH). Moreover, many of these solvents have very low flash points which render their use, on commercial scale, hazardous.
There exists a need therefore, for a method for obtaining Ramipril(I) of high optical purity which overcomes the shortcomings associated with the prior art methods.
An object of the present invention is to provide the process of preparation of optically pure Ramipril(I) having optical purity of at least 99.9% by crystallisation of optically impure Ramipril consisting of a mixture of undesired diastereomers up to 20%, from a solvent or a mixture of solvents selected from a group consisting of methyl formate, nitroalkanes, acetals and ethers.
It is another object of the present invention is to provide a novel hydrated form of Ramipril(I) which has, a distinct X-ray (powder) diffraction pattern, a distinct DSC thermogram, a distinct thermogravimetric curve and a distinct IR spectrum, which is different from the reported form of Ramipril(I).
A further object of the present invention is to provide a novel monohydrate form of Ramipril(I) having bulk density in the range of 0.2 to 0.24 g/ml.
A further object of the present invention is to provide anhydrous form of Ramipril(I) comprising of drying Ramipril monohydrate obtained above at a temperature of about 40° C. under reduce pressure of 2 to 5 mm Hg, it gives anhydrous Ramipril(I) of high bulk density (0.3-0.35 g/ml).
A further object of the invention is to provide a process for the preparation of monohydrate of Ramipril(I) comprising of crystallizing optically pure Ramipril(I) from water.
A further object of the present invention is to provide anhydrous form of Ramipril(I) comprising of drying Ramipril monohydrate obtained above at a temperature of about 40° C. under reduce pressure of 2 to 5 mm Hg, it gives anhydrous Ramipril(I) of high bulk density (0.3-0.35 g/ml).
A further object of the invention is to provide a process for the preparation of monohydrate of Ramipril(I) comprising of crystallizing optically pure Ramipril(I) from water.